Menopause in women's life is the most critical stage of the life when she undergoes dramatic physiological changes and is defined as the transition in women from reproductive to non-reproductive stage of life, which is due to the cessation of menstruation and occurs at an average age of fifty years. More particularly, the post-menopausal stage is characterized by the changes in the levels of circulating sex hormones, the most dramatic of which is the reduction in plasma levels of 17-beta-estradiol to less than ten percent of pre-menopausal values, which results in a number of chronic disorders and is often referred to as Post Menopausal Syndrome. In view of the fact that the current life span of women is about eighty years, women spend approximately one-third of their lives in the post-menopausal state. This means that the potential for chronic effects of the post-menopausal state on women's health is far greater today than at the turn of the century when life expectancy was considerably shorter.
Estrogen deficiency is the most important risk factor associated with Post Menopausal Syndrome. Some of the major effects of the Post Menopausal Syndrome that are source of greatest long-term medical concern include osteoporosis, bone loss, bone formation, cardiovascular effects more particularly hyperlipidaemia, thrombosis and vasomotor disorders, neurodegenerative effects such as stroke, senile dementia-Alzheimer type and Parkinson disease, menopausal symptoms including hot flushes, urogenital atrophy, depression, mania, schizophrenia, urinary incontinence, relief of dysmenorrhea; relief of dysfunctional uterine bleeding, an aid in ovarian development, treatment of acne, hirsutism.
Osteoporosis can be defined as a reduction in bone mass per unit volume with an alteration in bone microarchitecture that results in an increased susceptibility to fractures. It is not surprising that the most common fractures are those associated with bones, which are highly dependent on trabecular support, for example the vertebrae, the neck, and the weight bearing bone such as the femur, and the fore arm. Indeed the hip fracture, collies fractures and vertebrae crush fractures are hallmarks of post-menopausal osteoporosis. In most cases, bone loss occurs as a result of increased bone destruction (resorption) relative to bone formation and most women lose from about 20% to 60% of the bone mass in the trabecular compartment of the bone within 3 to 6 years after the menopause.
Osteoporosis, more particularly the post-menopausal osteoporosis represents a major problem in women health care and poses a risk to quality of life during old age. Efforts to reduce this risk factor and incidence of fractures have resulted in the development of compounds that conserve skeletal mass by inhibiting bone resorption and/or by enhancing bone formation (Dwivedi I, Ray S, 1995 “Recent developments in the chemotherapy of osteoporosis” Progress in Drug Research 45, 289-338, Editor E Jucker, Birkhauser Vela; Marshall D H, Horsmann A, Nordin B E C, 1977, “The prevention and management of post-menopausal osteoporosis” Acta Obstet Gynecol Scand (Suppl) 65:49-56; Hutchinson T A, Polansky S M, Feinstein A R, 1979, “Postmenopausal estrogen protect against fractures of hip and distal radius: A care-control study” Lancet 2:705-709. Estrogen replacement therapy also has positive effect on CVS & CNS related disorders (Lobo R A, 1990, “Cardiovascular implication of estrogen replacement therapy” Obstetrics & Gynaecology 75:185-245; Mendelson M E, Karas R H, 1994, “Estrogen and the blood vessel wall” Current opinion in Cardiology 1994:619-626; Stampfer M J, Colditz G A, 1991, “Estrogen replacement therapy and coronary heart disease: a quantitative assessment of the epidemiological evidence” Preventive Medicine 20:47-63).
Cardiovascular disease is another leading cause of morbidity and mortality in older women. Menopause and ageing increase risk of atherosclerosis and coronary artery disease. An altered lipid profile is thought to be associated with this increased risk. Compared to men, pre-menopausal women are relatively more protected from cardiovascular diseases. This protection is gradually lost following menopause. This loss of protection has been linked to the loss of estrogen and in particular to the loss of estrogen's stationary phase ability to regulate the level of serum lipids. The nature of estrogens ability to reduce serum lipids is not well understood, but evidences indicate that estrogen can up-regulate LDL receptors in the liver which act to remove excess cholesterol.
Additionally, estrogen appears to have some effects on the biosynthesis of cholesterol and other beneficial effects on cardiovascular health. Estrogen is also believed to directly influence vessel wall compliance, reduce peripheral resistance and prevent atherosclerosis. It is also reported that serum lipids in post-menopausal women having estrogen replacement therapy (ERT) return to concentrations found in the pre-menopausal state (Gruber C J, Tschugguel W, Schneeberger C, Huber J C, 2002, “Production and actions of estrogens” The New England Journal of Medicine 346:340-352; Bellino F L, Wise P M, 2003 “Nonhuman primate models of menopause workshop” Biology of Reproduction 68:10-18; Lobo R A 1990, “Cardiovascular implication of estrogen replacement therapy”, Obstetrics and Gynaecology 75:18S-24S; Medelson M E, Karas R D 1994, “Estrogen and the blood vessel wall”, Current opinion in Cardiology, 1994 (9): 619-626).
Based on available epidemiological data, the overall impact of these physiological and pharmacological actions of estrogen is an age independent reduction in cardiovascular mortality and morbidity in women (Knnel W H, Hjortland M, McNamara P M, 1976 “Menopause and risk of cardiovascular disease: The Framingham Study”, Ann Int Med 8:5447-5552). Furthermore, a more recent analysis has concluded that post-menopausal estrogen replacement therapy reduces the risk of cardiovascular disease by approximately 50 percent (Stampfer M J, Colditz G A, 1991, “Estrogen replacement therapy and coronary heart disease: a quantitative assessment of the epidemiological evidence”, Preventive Medicine 20:47-63).
There is growing interest in recent years on neuroprotective effects of estrogens for neurodegenerative conditions such as stroke, Alzheimer disease and Parkinson disease. Reports of greater brain damage in males than in females and in ovariectomized than intact female animals in ischemic stroke models are available. Estrogen is also known to increase density of N-methyl-D-aspartate receptors and increase neuronal sensitivity to input mediated by these receptors in neurons of hippocampus, the area involved in memory. The estradiol-depleted state in post-menopausal women has been correlated with increased incidence of stroke, cognitive defects, hot flashes, mood changes, and early onset and severity of Alzheimer disease. Some epidemiological data suggests that in post-menopausal women, estrogen deficiency is associated with decline in cognitive function and increased risk of Alzheimer's disease (Gruber C J, Tschugguel W, Schneeberger C, Huber J C, 2002 “Production and actions of estrogens”, The New England Journal of Medicine 346:340-352; Dhandapani K M, Brann D W, 2002, “Protective effects of estrogen and Selective Estrogen Receptor Modulators in the brain” Biology of Reproduction 67:1379-1385).
Short-term studies in human subjects have shown that increased levels of estrogen are associated with higher memory scores in post-menopausal women (Kampen D L, Sherwin B B, 1994 “Estrogen use and verbal memory in healthy postmenopausal women”, Obstetrics & Gynaecology 83:979-983; Ohkura T, Isse K, Akazawa K, Hamanioto M, Yoshimasa Y, Hagino N, 1995, “Long-term estrogen replacement therapy in female patients with dementia of the Alzheimer Type: 7 Case reports”, Dementia 6:99-107). Furthermore, the administration of exogenous estrogen to surgically post-menopausal women specially enhances short-term memory. Moreover, the effects as epidemiological findings indicate that estrogen treatment significantly decreases the risk of senile dementia-Alzheimer type in women (Paganini-Hill A, Henderson V W, 1994, “Estrogen deficiency and risk of Alzheimer's disease in women”, Am J Epidemiol 140:256-261; Ohkura T, Isse K, Akazawa K, Hamamoto M, Yoshimasa Y, Hagino N, 1995, “Long-term estrogen replacement therapy in female patients with dementia of the Alzheimer Type: 7 case reports”, Dementia 6:99-107).
While the mechanism whereby estrogens enhance cognitive function is unknown, it is possible to speculate that the direct effects of estrogen on cerebral blood flow (Goldman H, Skelley E b, Sandman C A, Kastin A J, Murphy S, 1976, “Hormones and regional brain blood flow”, Pharmacik Biochem Rev 5 (suppl 1):165-169; Ohkura T, Teshima Y, Isse K, Mastuda H, Inoue T, Sakai Y, Iwasaki N, Yaoi Y, 1995, “Estrogen increases cerebral and cerebellar blood flows in postmenopausal women”, Menopause: J North Am Menopause Soc 2:13-18) and neuronal cell activities (Singh M, Meyer E M, Simpkins J W, 1995, “The effect of ovariectomy and estradiol replacement on brain-derived neurotrophic factor messenger ribonucleic acid expression in cortical and hippocampal brain regions of female Sprague-Dawley rats”, Endocrinology 136:2320-2324; McMillan P J, Singer C A, Dorsa D M, 1996, “The effects of ovariectomy and estrogen replacement on trkA and choline acetyltransferase mRNA expression in the basal forebrain of the adult female Sprague-Dawley rat”, Neurosci 16:1860-1865).
Even though the beneficial effects of estrogen replacement on a wide variety of organ systems and tissues appear indisputable, the dose and duration of estrogen therapy is also associated with an increased risk of endometrial hyperplasia and carcinoma. The use of concomitant cyclic progestins does reduce the risk of endometrial pathology, but this is achieved at the expense of the return of regular uterine bleeding, a result that is objectionable to many patients. In addition to estrogen's stimulatory effect on the endometrium, there remains considerable controversy regarding reports of an association between long-term estrogen replacement and an increased risk of breast cancer (Bergkvist L, Adami H O, Persson I, Hoover R, Schairer C, 1989, “The risk of breast cancer after estrogen and estrogen-progestin replacement”, N Eng J Med, 321:293-297; Coiditz G A, Hankinson S E, Hunter D J, Willett W X, Manson J E, Stampfer M J, Hennekens C, Rosner B, Speizer F E, 1995, “The use of estrogens and progestins and the risk of breast cancer in postmenopausal women”, N Eng J Med 332:1593). Furthermore, there are other side effects of estrogen replacements, which, while might not be life threatening, contraindicate estrogen's use and reduce patient compliance.
Breast cancer is by far the most common malignant disease in women (22% of all new cancer cases). Concerted efforts are being made worldwide to develop new and safer drugs for the treatment of breast cancer. Tamoxifen (‘Nolvadex’), a selective estrogen receptor modulator (SERM), is currently the most widely used drug for the treatment of estrogen receptor positive (ER+ve) breast cancer. Tamoxifen inhibits the estrogen-dependent growth of cancer cells by competitive binding to estrogen receptors of the cells. However, as tamoxifen has also estrogen-like effects, it induces, among other adverse effects, endometrial cancer, deep vein thrombosis and pulmonary embolism in women undergoing the therapy. In addition, tamoxifen is known to induce DNA adduct formation and produced liver tumors in rodent life-term bioassays. Thus there is an urgent need for developing safer SERMs for the treatment of breast cancer (Baum M, Odling-Smee W, Houghton J, Riley D, Taylor H, 1994, “Endometrial cancer during tamoxifen treatment”, Lancet 343:1291; Clemons M, Danson S, Howell A, 2002, “Tamoxifen (‘Nolvadex’): Antitumour treatment. A review”, Cancer Treatment Reviews 28:165-180; Huggins, C, Yang N C, 1962, “Induction and extinction of mammary cancer”, Science 137:257-262; Williams G M, Latropoulos, M J, Djordjevic M V, Kaltenberg O P, 1993, “The triphenylethylene drug tamoxifen is a strong liver carcinogen in the rat”, Carcinogenesis 14:315-317; Meier C R, Jick H, 1998, “Tamoxifen and risk of idiopathic venous thromboembolism”, Br J Clin Pharmacol 45:608-612).
Egg-implantation in most mammals is dependent on a sequential action of estrogen and progesterone on the uterus and is considered as a preferential peripheral site for contraception. Development of hormone antagonists (both antiestrogens and antiprogestins) which inhibit action of endogenous hormones at the receptor level resulting in inhibition of implantation is one of the promising approaches for control or regulation of fertility in humans and other animals. Previous studies have revealed that administration of estrogen antagonists, recently termed as Selective Estrogen Receptor Modulators (SERMs), due to their tissue selective action) to cyclic or mated females prevents implantation.
Studies also reveal their uterine specific action, inhibiting endometrial receptivity to embryonic signal(s) for decidualisation, without affecting pre-implantation development of embryos up to the blastocyst stage (Singh M M, 2001, “Centchroman, a selective estrogen receptor modulator, as contraceptive and in the management of hormone related clinical disorders”, Medicinal Research Reviews 21:302-347; Nityanand S, Chandravati, Singh L, Srivastava J S, Kamboj V P, 1988, “Clinical evaluation of centchroman: A new oral contraceptive”, In: Hormone Antagonists for Fertility Regulation, Eds Puri C P, Van Look P FA, Indian Society for the Study of Reproduction and Fertility, Bombay, India, 223-230; Puri V, Kamboj V P, Chandra H, Ray S, Kole P L, Dhawan B N, Anand N, 1988, “Results of multicentric trial of centchroman”, In: Pharmacology for Health in Asia, Eds Dhawan B N, Agarwal K K, Arora R B, Parmar S S, Allied Publishers, New Delhi, 439-447; Nityanand S, Kamboj V P, Chandravati, Das K, Gupta K, Rohtagi P, Baveja R, Jina R, Mitra R, Sharma U, 1994, “Contraceptive efficacy and safety of centchroman with biweekly-cum-weekly schedule”, In: Current Concepts in Fertility Regulation and Reproduction, Eds Puri C P, Van Look P FA, Wiley Eastern Ltd., New Delhi, 61-68; Nityanand S, Gupta R C, Kamboj V P, Srivastava P K, Berry M, 1995, “Centchroman: Current Status as a contraceptive”, Indian Progress in Family Welfare 10:26-31; Nityanand S, Anand N, 1996, “Centchroman: A nonsteroidal antifertility agent”, FOGSI FOCUS, March issue: 8-10).
Such SERMs have also been successfully used for induction of ovulation in amenorrhic women under the assisted reproduction programmes (Roy S N, Kumari G L, Modoiya K, Prakash V, Ray S, 1976, “Induction of ovulation in human with centchroman, a preliminary report”, Fertility and Sterility 27:1108-1110) and suppression of post-partum lactation (Goodman and Gilman, The Pharmacological Basis of Therapeutics (Seventh Edition) Macmillan Publishing Company, 1985, pages 1321-1423).
From the foregoing discussion it would appear that the availability of therapies which possess the ideal pharmacological profile and could mimic the beneficial actions of estrogen on the bone, cardiovascular system and central nervous system without the undesirable side effects on uterus and breast, would essentially provide a “safe estrogen” which could dramatically influence the number of patients that would be able to benefit from estrogen replacement therapy. Therefore, in recognition of estrogen's beneficial effects on a number of body systems and disease conditions, there is a continuing need for the development of potent estrogen agonists which can selectively target different body tissues. Accordingly, the present invention provides new compounds, pharmaceutically acceptable salts and compositions thereof and methods of using such compounds for the prevention or treatment of:                (a) estrogen deficient or deprivation state in a mammal, in particular osteoporosis, bone loss, bone formation, cardiovascular effects more particularly hyperlipidaemia, thrombosis and vasomotor system, neurodegenerative effects such as stroke, senile dementia-Alzheimer type and Parkinson disease, menopausal symptoms including hot flushes, urogenital atrophy, depression, mania, schizophrenia and the like, urinary incontinence, relief of dysmenorrhea; relief of dysfunctional uterine bleeding, an aid in ovarian development, treatment of acne and hirsutism;        (b) estrogen dependent or estrogen independent cancers such as prostatic carcinoma, cancer of breast, cancer of uterus, cancer of the cervix and cancer of the colon;        (c) an aid in ovarian development or function;        (d) control or regulation of fertility in humans and in other animals;        (e) prevention of threatened or habitual abortion;        (f) suppression of post-partum lactation;        (g) physiological disorders such as obesity, depression etc.;        (h) regulation of glucose metabolism in non-insulin dependent diabetes mellitus.        